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We would like to congratulate Versteylen et al. (1) on their recent paper. In a relatively large cohort of 1,650 patients who underwent cardiac computed tomographic angiography (CCTA) for stable chest pain syndrome, the authors demonstrated that semiautomated coronary plaque quantification provided incremental value for the identification of patients at high risk for future acute coronary syndromes (ACS), surpassing that provided both by clinical risk profiling and by visual analysis of CCTA datasets (including calcium scoring, lumen narrowing, and number of coronary segments with noncalcified plaque). The authors suggest that such semiautomated plaque quantification can be implemented in the clinical routine, aiding the individualized prediction of ACS in patients with stable coronary artery disease (CAD).

In the past, several studies demonstrated visually-assessed CCTA parameters, including the extent of CAD, noncalcified plaque, and the number of coronary segments containing plaque, as robust independent predictors of cardiovascular events in patients with stable CAD (reviewed in Bamberg et al. [2]). On the other hand, in the recently published PEACE (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy) study, cardiac troponins were independent markers of cardiac outcomes in a large patient cohort (n = 3,623) with stable CAD and preserved left ventricular function (3). We previously demonstrated that high-sensitivity cardiac troponin T (hsTnT) is associated with quantitative characteristics of coronary plaque composition by CCTA in patients with stable CAD (4,5), suggesting that such increased hsTnT levels may be the consequence of repetitive clinically silent plaque ruptures in patients with a high extent of diffuse atherosclerotic disease. Although such phenomena may be present in presumably stable patients, preceding the clinical manifestation of infarction or sudden cardiac death, the underlying pathophysiologic mechanisms are not yet fully understood. Therefore, hsTnT-orientated therapeutic strategies have not been implemented in the clinical realm so far. In the present study, Versteylen et al. (1), for the first time to our knowledge in the current literature, provided the link between quantitative plaque composition assessment and clinical outcomes. Their study underscores the importance of objective and quantitative coronary plaque composition assessment, which may possibly represent the key for understanding the high risk for future cardiovascular events in the “vulnerable” patient with stable symptoms but high risk for future ACS.

Despite the comprehensive methodological approach, however, the present study has been conducted retrospectively and therefore has some limitations. First of all, it is not clear why only 101 randomly selected “controls” and not all 1,625 patients without ACS at follow-up were analyzed. The authors selected their controls out of 993 patients with CAD and without ACS, which may represent a serious selection bias because even patients with angiographically normal coronaries may present with ACS due to embolism of coronary atherothrombotic debris. Furthermore, the relatively high observer variability with quantification of noncalcified plaque is not consistent with previous reports (6). In addition, the time spent for such semiautomated measures was not mentioned by the authors. Despite these limitations, the study by Versteylen et al. (1) represents an important cornerstone toward the personalized risk assessment for future cardiac events in presumably stable CAD patients. This new type of quantitative analysis improved the prediction of cardiac outcomes, surpassing that provided by clinical risk profiling and by conventional CCTA readings (area under the curve rose from 0.64 to 0.79 with application of quantitative measures). Further studies are now warranted where the value of 1) clinical risk factors; 2) conventional CCTA findings; 3) quantitative measures of atherosclerotic plaque composition by CCTA; and 4) cardiac biomarkers, such as hsTnT, will be prospectively evaluated for the prediction of cardiac endpoints in patients with stable CAD. Possibly, and in light of the availability of a number of modern agents (including different P2Y12 inhibitors of different strengths, PCSK9 inhibitors with different low-density lipoprotein targets, high-density lipoprotein modifiers, and soluble receptor for advanced glycation endproducts modulating agents targeting vascular inflammation), cardiac biomarkers such as the hsTnT may present novel therapeutic targets in future interventional pharmacotherapy studies. Thus, patients with increased atherosclerotic burden, identified as high-risk candidates for future ACS, may undergo combined treatment with 1 or several of the above-mentioned agents. In light of the fact that CCTA acquisitions currently require a radiation exposure comparable to that of calcium scoring (1.0 to 1.5 mSv), longitudinal CCTA studies may be able to noninvasively monitor mechanisms of plaque regression during pharmacologic intervention.

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